Topical delivery of anti-alopecia agents

ABSTRACT

The present invention provides a topical drug delivery system which comprises: a therapeutically effective amount of an anti-alopecia agent; at least one dermal penetration enhancer, which is a safe skin-tolerant ester sunscreen ester; and a volatile liquid. The invention also provides a method for administering at least one systemic acting anti-alopecia agent to an animal which comprises applying an effective amount of the anti-alopecia agent in the form of the drug delivery system of the present invention.

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/910,780, filed Jul. 24, 2001, now U.S. Pat. No. 6,818,226which is a divisional of U.S. Pat. No. 6,299,900, filed Dec. 18, 1998 asthe U.S. national stage applicatlon of PCT application PCT/AU97/00091,filed Feb. 19, 1997. The entire contents of each of U.S. patentapplication Ser. No. 09/910,780, U.S. Pat. No. 6,299,900, and PCTapplication PCT/AU97/00091 are incorporated herein by reference, andpriority to each is claimed under 35 U.S.C. § 119 and/or § 120.

FIELD OF THE INVENTION

The present invention relates to topical drug delivery. Morespecifically, the invention relates to a topical absorption/penetrationenhancing agent for use in the delivery of anti-alopecia agents andanti-alopecia agent derivatives to an animal, including a human. Theinvention also relates to a system for the non-occlusive delivery to ananimal of anti-alopecia agents and anti-alopecia agent derivativesacross a dermal surface of the animal.

BACKGROUND OF THE INVENTION

There is a constant need for methods for the safe and effectiveadministration of physiologically active agents, such as anti-alopeciaagents. For many medications it is important that the administrationregime is as simple and non-invasive as possible in order to maintain ahigh level of compliance by the patient.

Oral administration is one particular regime that is commonly usedbecause it is a relatively simple to follow. However, the oraladministration route is also complicated because of complicationsassociated with gastrointestinal irritation and with drug metabolism inthe liver. These complications may result in side effects, includingmood disturbance (Altomare et al., 2002, J Dermatol. 29(10):665-9),unilateral gynecomastia (Ferrando et al., 2002, Arch Dermatol.138(4):543-4), decreased libido, erectile dysfunction and ejaculationdisorder as reported for the oral administration of finasteride(McClellan et al., 1999, Drugs 57(1):111-26).

Administration of physiologically active agents through the skin(‘topical drug delivery’) has received increased attention because itnot only provides a relatively simple dosage regime but it also providesa relatively slow and controlled route for release of a physiologicallyactive agent into the local tissue. However, topical drug delivery iscomplicated by the fact that the skin behaves as a natural barrier andtherefore transport of agents through the skin is a complex mechanism.

Structurally, the skin consists of two principle parts, a relativelythin outermost layer (the ‘epidermis’) and a thicker inner region (the‘dermis’). The outermost layer of the epidermis (the ‘stratum corneum’)consists of flattened dead cells which are filled with keratin. Theregions between the flattened dead cells of the stratum corneum arefilled with lipids which form lamellar phases that are responsible forthe natural barrier properties of the skin.

For effective local delivery of a physiologically active agent appliedto the surface of the skin (‘topical application’), the agent must bepartitioned firstly from the vehicle into the stratum corneum, it musttypically then be diffused within the stratum corneum before beingpartitioned from the stratum corneum to the local tissues including theviable epidermis, dermis, subcutis and appendageal.

To overcome some of the problems with topical delivery that areassociated with transport across the dermal layers (‘percutaneousabsorption’), physiologically active agents are commonly formulated withincorporation of one or more dermal penetration enhancers which areoften lipophilic chemicals that readily partition into the stratumcorneum whereupon they exert their effects on improving the transport ofdrugs across the skin barrier (Finnin et al., 1999, J.Pharm Sci.,88(10), 755-758).

There is a need for improved compositions for topical delivery ofanti-alopecia agents.

SUMMARY

According to the present invention there is provided a topical drugdelivery system which comprises:

a. a therapeutically effective amount of an anti-alopecia agent;

b. at least one dermal penetration enhancer, which is a safeskin-tolerant ester sunscreen of formula (I):

-   -    wherein:    -   R¹ is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy or        NR³R⁴;    -   R² is a C₈ to C₁₈ alkyl,    -   R³ and R⁴ are each independently hydrogen, lower alkyl or R³ and        R⁴ together with the nitrogen atom to which they are attached        form a 5- or 6-membered heterocyclic ring;    -   n is 0 or 1, and    -   q is 1 or 2,    -   wherein when n is 0 and R¹ is NR³ R⁴, then NR³ R⁴ is        para-substituted; and wherein said dermal penetration enhancer        is present in an amount of from about 10 to about 10,000 wt %        based on the weight of the anti-alopecia agent; and

c. at least one volatile liquid.

In addition to providing improved percutaneous absorption efficiency,the composition of the invention may also provide lower irritancy thansome other more occlusive delivery systems such as transdermal patches,because the composition is non-occlusive to the skin.

More preferably the dermal penetration enhancer is selected from thegroup consisting of a C₈ to C₁₈ alkyl para-aminobenzoate, C₈ to C₁₈alkyl dimethyl-para-aminobenzoate, C₈ to C₁₈ alkyl cinnamate, C₈ to C₁₈alkyl methoxycinnamate or C₈ to C₁₈ alkyl salicylate. Most preferablythe dermal penetration enhancer is octyl salicylate, octyl dimethylpara-aminobenzoate or octyl para-methoxycinnamate (Padimate O).

The drug delivery systems according to the invention may comprise one ormore anti-alopecia agents together with the penetration enhancerincorporated into a dosage form for topical application to the skin ofanimals.

Suitable dosage forms include creams, lotions, gels, ointments, mousses,sprays, aerosols, or any one of a variety of topical devices for use inthe continuous administration of locally active drugs by absorption intothe skin. Some examples of suitable vehicles are given in U.S. Pat. Nos.3,598,122, 3,598,123, 3,742,951, 3,814,097, 3,921,636, 3,993,072,3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,201,211,4,230,105, 4,292,299, 4,292,303, 5,323,769, 5,023,085, 5,474,783,4,941,880 and 4,077,407. These disclosures are thus hereby incorporatedherein by reference.

Optionally the drug delivery system may contain pharmaceuticalcompounding agents, such as one or more thickening agents such ascellulosic thickening agents, ethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, povidone, polyacrylic acids such ascarbopol, Sepigel® (polyacrylamide/isoparaffin/laureth-7), the Gantrez®series of polymethyl vinyl ether/maleic anhydride copolymers such as thebutyl ester of PVM/MA copolymer Gantrez® A-425, and any thickening agentknown in the art that has good compatibility with the volatile liquidand enhancers of the present invention.

Anti-alopecia agents that may be used in the drug delivery system of thepresent invention include any anti-alopecia agents which are compatiblewith the dermal penetration enhancers of the present invention and whichcan be delivered through the skin with the assistance of the dermalpenetration enhancer to achieve the desired effect. Suitableanti-alopecia agents include, but are not limited to, minoxidil,cromakalin, pinacidil, naminidil, diphenylcyclopropenone, tricomin,antiandrogen agents such as cyproterone acetate, danazol and flutamide,5-alpha reductase inhibitors such as finasteride, turosteride,LY-191704, MK-306 and dutasteride (U.S. Pat. No. 4,377,584), and thosecompounds selected from the classes of s-triazines, benzopyrans,pyridinopyrans and thiane-1-oxides or pharmaceutically acceptable saltsor derivatives of any one of the aforementioned.

In one preferred form of the invention the drug delivery systemcomprises on a weight basis from about 0.1 to about 10% of theanti-alopecia agent, from about 0.1 to 10% of the at least one dermalpenetration enhancer and from about 45 to 99.8% of a volatile liquid. Inanother preferred form the volatile liquid is ethanol, isopropanol ormixture thereof in the range of about 80 to 98%.

In yet another preferred form of the invention the drug delivery systemcomprises, on a weight basis, from about 1 to 5% of an anti-alopeciaagent, from about 1 to 5% of the dermal penetration enhancer, from about45 to 90% ethanol, isopropanol or mixture thereof, 5 to 45% water; andoptionally 0.5 to 5% of a thickening agent.

Whilst it is preferred that the anti-alopecia agent and penetrationenhancer be delivered by simultaneous administration, the penetrationenhancer may be applied before or after the application of theanti-alopecia agent, if desired.

The present invention also provides a method for administering at leastone systemic or locally acting anti-alopecia agent to an animal whichcomprises applying an effective amount of the anti-alopecia agent in theform of the drug delivery system of the present invention.

Preferably the animal is a human but the invention also extends to thetreatment of non-human animals.

Preferably the drug delivery system is not supersaturated with respectto the anti-alopecia agent. As the volatile liquid of the drug deliverysystem evaporates, the resulting non-volatile composition is rapidlydriven into the dermal surface. It is possible that as the volatileliquid evaporates, the non-volatile dermal penetration enhancer becomessupersaturated with respect to the anti-alopecia agent. However, it ispreferred that any supersaturation does not occur before transport ofthe resulting non-volatile composition across the epidermal surface hasoccurred.

It is most desirable that, after application of the drug deliverysystem, the volatile component of the delivery system evaporates and thearea of skin to which the drug delivery system was applied becomestouch-dry. Preferably said area of skin becomes touch-dry within 10minutes, more preferably within 3 minutes, most preferably within 1minute.

The group of dermal penetration enhancing ester sunscreen compounds ofthe present invention are particularly suitable for topical deliveryanti-alopecia agents through the skin of an animal. These dermalpenetration enhancing compounds are of low toxicity to the skin and areexcellent promoters of percutaneous absorption.

Preferred volatile liquids of the present invention include safeskin-tolerant solvents such as ethanol and isopropanol. An aerosolpropellant, such as dimethyl ether, may constitute a volatile liquid forthe purpose of the present invention.

Surprisingly the group of dermal penetration compounds identifiedenhance the absorption of anti-alopecia agents through the skin whileavoiding the significant pharmacological disadvantages and toxicities ofprior art enhancers. Additionally, the group of compounds of theinvention surprisingly exhibit appreciable penetration into andsubstantivity for the outer layers of the skin, namely the stratumcorneum which has previously presented a formidable barrier topercutaneous drug absorption.

In drug delivery systems according to the present invention apharmaceutical compounding agent, co-solvent, surfactant, emulsifier,antioxidant, preservative, stabiliser, diluent or a mixture of two ormore of said components may be incorporated in these systems as isappropriate to the particular route of administration and dosage form.The amount and type of components used should be compatible with thedermal penetration enhancers of this invention as well as with theanti-alopecia agent. A co-solvent or other standard adjuvant, such as asurfactant, may be required to maintain the anti-alopecia agent insolution or suspension at the desired concentration.

The pharmaceutical compounding agents can include paraffin oils, esterssuch as isopropyl myristate, ethanol, silicone oils and vegetable oils.These are preferably used in the range 1 to 50%. Surfactants such asethoxylated fatty alcohols, glycerol mono stearate, phosphate esters,and other commonly used emulsifiers and surfactants preferably in therange of 0.1 to 10% may be used, as may be preservatives such ashydroxybenzoate esters for preservation of the compound preferably inamounts of 0.01% to 0.5%. Typical co-solvents and adjuvants may be ethylalcohol, isopropyl alcohol, acetone, dimethyl ether and glycol etherssuch as diethylene glycol mono ethyl ether. These may be used in amountsof 1 to 50%.

Because of the effect of the penetration enhancer of the invention, thedosage of the anti-alopecia agent may often be less than thatconventionally used. It is proposed that, a dosage near the lower end ofthe useful range of the particular anti-alopecia agent may be employedinitially and increased as indicated from the observed response ifnecessary.

The concentration of anti-alopecia agent used in the drug deliverysystem will depend on its properties and may be equivalent to thatnormally utilised for the particular anti-alopecia agent in conventionalformulations. Both the amount anti-alopecia agent and the amount ofpenetration enhancer will be influenced by the type of effect desired.

Where it is desired to achieve higher local concentration of ananti-alopecia agent, proportionately higher concentrations of theenhancer of the invention may be required in the topical drug deliverysystem of the present invention, and the amount of anti-alopecia agentincluded in the composition should be sufficient to provide the tissuelevel desired.

The concentration of absorption/penetration enhancer may be in the rangefrom 10-10,000 weight percent of absorption/penetration enhancer basedupon the weight of anti-alopecia agent. The ratio of penetrationenhancer to anti-alopecia agent may vary considerably and will begoverned as much as anything, by the pharmacological results that arerequired to be achieved. In principle, it is desirable that as littleabsorption enhancer as possible is used. On the other hand, for someanti-alopecia agents, it may well be that the upper range of 10,000% byweight will be required. It is preferred that the penetration enhancerand anti-alopecia agent are in approximately equal proportions.

A particular advantage of the drug delivery system of the presentinvention is that patient compliance is improved as the system does notocclude the skin. As a result local irritation and allergicsensitization problems arising from prolonged exposure of the skin toboth the delivery system of occlusive transdermal patch devices and theadhesive used to affix these patches to the skin are reduced.

The following definitions apply through this description and the claimswhich follow.

The term “comprise” or variations such as “comprising” and “comprises”will be understood to imply the inclusion of a stated integer or groupof integers but not the exclusion of any other integer or group ofintegers.

The terms “topical” and “transdermal” are used herein in the broadestsense to refer to being able to pass through unbroken skin.

The term “dermal penetration enhancer” is used herein in its broadestsense to refer to an agent which improves the rate of percutaneoustransport of active agents across the skin or use and delivery of activeagents to organisms such as animals, whether it be for local applicationor systemic delivery.

The term “non-occlusive” is used herein in its broadest sense to referto not trapping or closing the skin to the atmosphere by means of apatch device, fixed reservoir, application chamber, tape, bandage,sticking plaster, or the like which remains on the skin at the site ofapplication for a prolonged length of time.

The term “stratum corneum” is used herein in its broadest sense to referto the outer layer of the skin, which is comprised of (approximately 15)layers of terminally differentiated keratinocytes made primarily of theproteinaceous material keratin arranged in a ‘brick and mortar’ fashionwith the mortar being comprised of a lipid matrix made primarily fromcholesterol, ceramides and long chain fatty acids. The stratum corneumcreates the rate-limiting barrier for diffusion of the active agentacross the skin.

The term “skin-depot” is used herein in its broadest sense to refer to areservoir or deposit of active agent and dermal penetration enhancerwithin the stratum corneum, whether it be intra-cellular (withinkeratinocytes) or intercellular.

The term “volatile:non-volatile liquid vehicle” is used in the art torefer to a liquid pharmaceutical vehicle comprising a volatile liquidmixed with a non-volatile liquid vehicle, such as a dermal penetrationenhancer. A system or vehicle comprising a volatile liquid mixed with anon-volatile dermal penetration enhancer when described herein is usedin its broadest sense to include those systems known asvolatile:non-volatile liquid vehicles.

Alkyl and alkoxy groups referred to herein may be either straight chainor branched. The term “lower alkyl” means alkyl groups containing from 1to 5 carbon atoms. The term lower alkoxy has a similar meaning. The term“long chain alkyl” means alkyl groups containing from 5 to 18 carbonatoms, more preferably 6 to 18 carbon atoms. The term “halide” meansfluoride, chloride, bromide or iodide. The term “heterocyclic ring” isherein defined to mean a ring of carbon atoms containing at least onehetero atom, and further the ring may be saturated or unsaturated to anyallowable degree.

The term “sunscreen” is used herein in its broadest sense to refer to achemical agent capable of filtering out ultraviolet light.

The drug delivery system of the present invention enables a wide rangeof anti-alopecia agents to be delivered through the skin to achieve adesired systemic effect. The drug delivery system preferably comprisesthe anti-alopecia agent intimately mixed with a non-volatile dermalpenetration enhancer and a volatile liquid. Where the drug deliverysystem is applied to the skin, the anti-alopecia agent and non-volatileliquid are thermodynamically driven into the skin as the volatile liquidevaporates. Once within the skin the non-volatile liquid may eitherdisrupt the lipid matrix and/or act as a solubilizer to allow anenhanced penetration rate of the anti-alopecia agent through the skinand into the subject being treated. In this way, the dermal penetrationenhancer acts as a vehicle and many systemic active anti-alopecia agentsare able to be percutaneously administered to an animal.

It is believed that the non-volatile dermal penetration enhancer isreadily absorbed into the stratum corneum in sufficient quantities toform a reservoir or depot of the dermal penetration enhancer within thestratum corneum. The dermal penetration enhancer also contains theanti-alopecia agent to be administered and as the dermal penetrationenhancer crosses into the skin to form the skin-depot, the anti-alopeciaagent contained therein is transported through the skin and containedwithin the depot. These depots are believed to form within the lipidmatrix of the stratum corneum wherein the lipid matrix creates arate-limiting barrier for diffusion of the anti-alopecia agent acrossthe skin and allows the dermally administered anti-alopecia agent to betopically released over a period of time, usually up to 24 hours.

Once the volatile liquid of the drug delivery system has evaporated,driving the mixture of non-volatile dermal penetration enhancer andanti-alopecia agent into the stratum corneum, the outer surface of theskin is then substantially free of anti-alopecia agent and non-volatiledermal penetration enhancer. Normal touching, wearing of clothes,rinsing or even washing of the skin will not, to any significant extent,affect delivery of the anti-alopecia agent or displace either theanti-alopecia agent or the non-volatile dermal penetration enhancer,once the volatile liquid has evaporated.

This is in contrast to prior-art systems where supersaturated solutionsare used to increase the rate of drug permeation across the skin. Suchsupersaturated solutions are susceptible of ready precipitation andrequire stabilization, such as with polymers, or protection fromexternal surfaces or objects which may effect nucleation.

The rate of absorption of the anti-alopecia agent via the stratumcorneum is increased by the non-volatile dermal penetration enhancer.The anti-alopecia agent may be dissolved or suspended in the dermalpenetration enhancer at the time when it is being transported from thesurface of the skin and into the stratum corneum. The performance of thedermal penetration enhancer to deliver a desired anti-alopecia agentvaries with differences in both the nature of the dermal penetrationenhancer and the anti-alopecia agent. It is understood that differentdermal penetration enhancers may need to be selected to be appropriatefor delivery of various anti-alopecia agents.

Diseases or conditions that may be treated by using the drug deliverysystem and methods of the present invention include, but are not limitedto, alopecia due to the expanding understanding of the benefit ofanti-alopecia agents for such purposes, hair loss, baldness, hairbreakage, psoriasis, itchiness of scalp and other scalp problems inwomen and men.

The drug delivery system of the present invention may be applied to theskin by means of an aerosol, spray, pump-pack, brush, swab, or otherapplicator for the dosing of topical liquids.

DETAILED DESCRIPTION

The invention will now be described with reference to the followingexamples and accompanying FIGURE. The examples and figure are not to beconstrued as limiting the invention in any way. They are included tofurther illustrate the present invention and advantages thereof.

In the accompanying FIGURE:

FIG. 1 Shows the cumulative amount of finasteride penetrating acrosshuman epidermis (μg/cm²) versus time (hours) for the topical solutioncomposition 1A with or without the dermal penetration enhancer, octylsalicylate. Error bars represent Standard Error of the Mean (SEM).

In the examples, the effectiveness of the penetration enhancers isillustrated by measuring the skin penetration of formulationsincorporating a number of anti-alopecia agents with the dermalpenetration enhancers. Also, the skin penetration of anti-alopeciaagents was measured with formulations of the anti-alopecia agents withcommon adjuvants, which serve as control formulations. The comparisonsmade generally consisted of measuring the relative penetration throughhuman skin of the various formulations. In every case, thoseformulations which contained the dermal penetration enhancers deliveredmore of the anti-alopecia agent through the skin than did thecorresponding control formulation.

EXAMPLE 1

Topical compositions

Composition 1A Composition 1B Component Amount Component AmountFinasteride 0.2% w/v Finasteride 0.2% w/v Aqueous ethanol to 100 mLOctyl salicylate   5% w/v (95% v/v) Aqueous ethanol to 100 mL (95% v/v)

As shown in FIG. 1 the addition of the safe sunscreen ester dermalpenetration enhancer, octyl salicylate, surprisingly caused a marked10-fold increase in the transdermal delivery of finasteride across theskin (p<0.01).

The diffusion experiments were performed using human epidermis as themodel membrane. These experiments were performed over 24 h withstainless steel, flow-through diffusion cells based on those previouslydescribed, (Cooper, 1984, J. Pharm. Sci., 73, 1153-1156.) except thatthe cell was modified to increase the diffusional area to 1.0 cm². Afinite dose of 100 μl/cm² of the formulation was applied to thediffusion cell and left uncovered for the diffusion of the experiment. Apiece of stainless steel wire mesh was placed directly below the skin inthe receptor chamber of the diffusion cell to maintain a turbulent flowof receptor solution below the skin. The diffusion cells were maintainedat a flow rate of approximately 1.0 mL/cm²/h by a microcassetteperistaltic pump (Watson Marlow 505S, UK). The cells were kept at32±0.5° C. by a heater bar and the samples are collected intoappropriately sized plastic vials on an automated fraction collector(Isco Retriever II, Lincoln, Nebr.) at specified intervals. The receptorsolution (10% ethanol in water with 0.002% w/v sodium azide) maintainedsink conditions beneath the skin.

Samples were analysed for finasteride directly by RP-HPLC using thefollowing conditions; [Column—Waters Symmetry C₁₈ column (3.9×150 mm)with a 5 μm support size; Mobile phase—45% Acetonitrile/55% water; Flowrate 1 mL/min; Absorbance—210 nm; and Injection volume—200 μL].

EXAMPLE 2

Topical compositions

Composition 2A Composition 2B Component Amount Component AmountFlutamide 0.2% w/v Flutamide 0.2% w/v Aqueous ethanol to 100 mL Octylsalicylate   5% w/v (95% v/v) Aqueous ethanol to 100 mL (95% v/v)

1. A transdermal drug delivery system which comprises: a. atherapeutically effective amount of an anti-alopecia agent; b. at leastone dermal penetration enhancer, which is a safe skin-tolerant estersunscreen of formula (I):

 wherein R¹ is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy orNR³ R⁴, R² is a C₈ to C₁₈ alkyl, R³ and R⁴ are each independentlyhydrogen, lower alkyl or R³ and R⁴ together with the nitrogen atom towhich they are attached form a 5- or 6-membered heterocyclic ring; n is0 or 1, and q is 1 or2, wherein when n is 0 and R¹ is NR³ R⁴, then NR³R⁴ is para-substituted; and wherein said dermal penetration enhancer ispresent in an amount of from about 10 to about 10,000 wt % based on theweight of the anti-alopecia agent; and c. a volatile liquid.
 2. Atransdermal drug delivery system according to claim 1, wherein thedermal penetration enhancer is octyl salicylate.
 3. A transdermal drugdelivery system according to claim 2, wherein the anti-alopecia agent isselected from the list consisting of minoxidil, cromakalin, pinacidil,naminidil, diphenylcyclopropenone, cyproterone acetate, danazol,tricomin, turosteride, LY-191704, MK-306, dutasteride and thosecompounds selected from the classes of s-triazines, benzopyran,pyridinopyran and thiane-1-oxides or pharmaceutically acceptable saltsor derivatives of any one of the aforementioned.
 4. A transdermal drugdelivery system according to claim 2, wherein the anti-alopecia agent isa 5-alpha reductase inhibitor.
 5. A transdermal drug delivery systemaccording to claim 4, wherein the 5-alpha reductase inhibitor isfinasteride.
 6. A transdermal drug delivery system according to claim 2,wherein the anti-alopecia agent is an antiandrogen.
 7. A transdermaldrug delivery system according to claim 6, wherein the antiandrogen isflutamide.
 8. A transdermal drug delivery system according to claim 1,wherein the volatile liquid is ethanol, isopropanol or mixture thereof.9. A transdermal drug delivery system according to claim 8 comprising ona weight basis: a. from about 0.1 to about 10% of the anti-alopeciaagent; b. from about 1 to 10% of the dermal penetration enhancer; and c.from about 45 to 99.8% ethanol, isopropanol or mixture thereof.
 10. Atransdermal drug delivery system according to claim 8 comprising on aweight basis: a. from about 0.1 to about 6% of the anti-alopecia agent;b. from about 1 to 10% of the dermal penetration enhancer; and c. fromabout 80 to 98% ethanol, isopropanol or mixture thereof.
 11. Atransdermal drug delivery system according to claim 8 which comprises ona weight basis: a. 0.1 to 6% finasteride; b. from about 1 to 10% octylsalicylate; and c. from about 80 to 98% Alcohol USP (95% ethanol).
 12. Atransdermal drug delivery system according to claim 8 which comprises ona weight basis: a. 0.1 to 5% finasteride; b. from about 1 to 5% octylsalicylate; and c. from about 45 to 90% ethanol, isopropanol or mixturethereof; d. 5 to 45% water; and e. 0.5 to 5% of a thickening agent. 13.A method for administering at least one systemic acting anti-alopeciaagent to an animal which comprises applying an effective amount of theanti-alopecia agent in the form of a drug delivery system according toclaim
 1. 14. A method according to claim 13, wherein the anti-alopeciaagent is finasteride.
 15. A method according to claim 14, wherein thedrug delivery system is applied to the skin of the human or animalcovering a delivery surface area between 10 and 800 cm².
 16. A methodaccording to claim 14, wherein the drug delivery system is applied tothe skin of the human or animal covering a delivery surface area between10 and 400 cm².
 17. A method according to claim 14, wherein the drugdelivery system is applied to the skin of the human or animal covering adelivery surface area between 10 and 200 cm².
 18. A method according toclaim 14, wherein the drug delivery system is applied using a fixed orvariable metered dose applicator.